Persistent activity states (attractors), observed in several neocortical areas after the removal of a sensory stimulus, are believed to be the neuronal basis of working memory. One of the possible mechanisms that can underlie persistent activity is recurrent excitation mediated by intracortical synaptic connections. A recent experimental study revealed that connections between pyramidal cells in prefrontal cortex exhibit various degrees of synaptic depression and facilitation. Here we analyze the effect of synaptic dynamics on the emergence and persistence of attractor states in interconnected neural networks. We show that different combinations of synaptic depression and facilitation result in qualitatively different network dynamics with respect to the emergence of the attractor states. This analysis raises the possibility that the framework of attractor neural networks can be extended to represent time-dependent stimuli.

We describe a phenomenon of hyperpolarization-activated graded persistent activity (HAGPA) in prefrontal cortex neurons. Successive hyperpolarizing pulses induced increasingly higher rates of tonic firing that remained stable for tens of seconds, allowing the neuron to retain a memory of the previous history of stimulation. This phenomenon occurred at the cellular level and in the absence of neuromodulators. Neurons with HAGPA had a sag during hyperpolarization, and blocking h-current eliminated the sag and prevented HAGPA, suggesting that the activation of this hyperpolarization-activated cationic current was necessary for the occurrence of the phenomenon. A single-neuron biophysical model including h-current modulation by intracellular calcium was able to display HAGPA. This form of neuronal memory not only allows the transformation of inhibition into an increase of firing rate, but also endows neurons with a mechanism to compute the properties of successive inputs into persistent activity, thus solving a difficult computational problem.

Neurophysiological experiments on monkeys have reported highly irregular persistent activity during the performance of an oculomotor delayed-response task. These experiments show that during the delay period the coefficient of variation (CV) of interspike intervals (ISI) of prefrontal neurons is above 1, on average, and larger than during the fixation period. In the present paper, we show that this feature can be reproduced in a network in which persistent activity is induced by excitatory feedback, provided that (i) the post-spike reset is close enough to threshold , (ii) synaptic efficacies are a non-linear function of the pre-synaptic firing rate. Non-linearity between pre-synaptic rate and effective synaptic strength is implemented by a standard short-term depression mechanism (STD). First, we consider the simplest possible network with excitatory feedback: a fully connected homogeneous network of excitatory leaky integrate-and-fire neurons, using both numerical simulations and analytical techniques. The results are then confirmed in a network with selective excitatory neurons and inhibition. In both the cases there is a large range of values of the synaptic efficacies for which the statistics of firing of single cells is similar to experimental data.

Neural integrators and working memory rely on persistent activity, a widespread neural phenomenon potentially involving persistent sodium conductances. Using a unique combination of voltage-clamp, dynamic-clamp, and frequency-domain techniques, we have investigated the role of voltage-dependent conductances on the dendritic electrotonic structure of neurons of the prepositus hypoglossi nucleus (PHN), which is known to be involved in oculomotor integration. The PHN contains two main neuronal populations: type B neurons with a double afterhyperpolarization and type D neurons, which not only are oscillatory but also have a greater electrotonic length than that of type B neurons. The persistent sodium conductance is present in all PHN neurons, although its effect on the dynamic electrotonic structure is shown to significantly differ in the two major cell types present in the nucleus. The electrotonic differences are such that the persistent sodium conductance can be almost perfectly manipulated in a type B neuron using an on-line dynamic clamp to add or subtract virtual sodium ion channels. The dynamic-clamp results are confirmed by data-fitted models, which suggest that the persistent sodium conductance has two different roles depending on its somatic versus dendritic location: perisomatic conductances could play a major role in maintaining action potential discharge and dendritic conductances would be more involved in other computational properties...

Persistent activity observed in neurophysiological experiments in monkeys is thought to be the neuronal correlate of working memory. Over the last decade, network modellers have strived to reproduce the main features of these experiments. In particular, attractor network models have been proposed in which there is a coexistence between a non-selective attractor state with low background activity with selective attractor states in which sub-groups of neurons fire at rates which are higher (but not much higher) than background rates. A recent detailed statistical analysis of the data seems however to challenge such attractor models: the data indicates that firing during persistent activity is highly irregular (with an average CV larger than 1), while models predict a more regular firing process (CV smaller than 1). We discuss here recent proposals that allow to reproduce this feature of the experiments.

Since its first discovery in the prefrontal cortex, persistent activity during the interval between a transient sensory stimulus and a subsequent behavioral response has been identified in many cortical and subcortical areas. Such persistent activity is thought to reflect the maintenance of working memory representations that bridge past events with future contingent plans. Indeed, the term persistent activity is sometimes used interchangeably with working memory. In this review, we argue that persistent activity observed broadly across many cortical and subcortical areas reflects not only working memory maintenance, but also a variety of other cognitive processes, including perceptual and reward-based decision making.

We combined in vitro intracellular recording from prefrontal cortical neurons with simulated synaptic activity of a layer 5 prefrontal microcircuit using a dynamic clamp. During simulated in vivo background conditions, the cell responded to a brief depolarization with a sequence of spikes that outlasted the depolarization, mimicking the activity of a cell recorded during the delay period of a working memory task in the behaving monkey. The onset of sustained activity depended on the number of action potentials elicited by the cue-like depolarization. Too few spikes failed to provide enough NMDA drive to elicit sustained reverberations; too many spikes activated a slow intrinsic hyperpolarization current that prevented spiking; an intermediate number of spikes produced sustained activity. When high dopamine levels were simulated by depolarizing the cell and by increasing the amount of NMDA current, the cell exhibited spontaneous ‘up-states’ that terminated by the activation of a slow intrinsic hyperpolarizing current. The firing rate during the delay period could be effectively modulated by the standard deviation of the inhibitory background synaptic noise without significant changes in the background firing rate before cue onset. These results suggest that the balance between fast feedback inhibition and slower AMPA and NMDA feedback excitation is critical in initiating persistent activity and that the maintenance of persistent activity may be regulated by the amount of correlated background inhibition.

The anterodorsal nucleus of the thalamus contains a high percentage of head-direction cells whose activities are correlated with an animal’s directional heading in the horizontal plane. The firing of head-direction cells could involve self-sustaining reverberating activity in a recurrent network, but the thalamus by itself lacks strong excitatory recurrent synaptic connections to sustain tonic reverberating activity. Here we examined whether a single thalamic neuron could sustain its own activity without synaptic input by recording from individual neurons from anterodorsal thalamus in brain slices with synaptic blockers. We found that the rebound firing induced by hyperpolarizing pulses often decayed slowly so that a thalamic neuron could keep on firing for many minutes after stimulation. The hyperpolarization-induced persistent firing rate was graded under repeated current injections, and could be enhanced by serotonin. The effect of depolarizing pulses was much weaker and only slightly accelerated the decay of the hyperpolarization-induced persistent firing. Our finding provides the first direct evidence for single-cell persistent activity in the thalamus, supporting the notion that cellular mechanisms at the slow time scale of minutes might potentially contribute to the operations of the head-direction system.

We assessed the contribution of four baseline markers—HLA-DRB1 shared epitope (SE), −308 tumor necrosis factor α gene promoter polymorphism, rheumatoid factor, and anticitrullinated peptide antibodies—for predicting persistent activity (DAS28 score ≥2.6) after one year of followup in a cohort of 201 patients with recent-onset rheumatoid arthritis (RA) or undifferentiated arthritis (UA) aged 16 years or older who had a 4-week to 12-month history of swelling of at least two joints. Patients had not been previously treated with corticosteroids or disease-modifying antirheumatic drugs (DMARD). In the best logistic regression model, only two variables were retained: SE positivity and number of DMARD administered (area under the curve = 76.4%; 95% CI: 69.2%, 84.4%; P < 0.001). The best linear regression model also included these two variables, explaining only 22.5% of the variability of DAS28 score. In this study, given an equal number of DMARD administered, the probability of persistent activity in patients with recent-onset RA or UA was significantly influenced by SE presence.

Proper functioning of working memory involves the expression of stimulus-selective persistent activity in pyramidal neurons of the prefrontal cortex (PFC), which refers to neural activity that persists for seconds beyond the end of the stimulus. The mechanisms which PFC pyramidal neurons use to discriminate between preferred vs. neutral inputs at the cellular level are largely unknown. Moreover, the presence of pyramidal cell subtypes with different firing patterns, such as regular spiking and intrinsic bursting, raises the question as to what their distinct role might be in persistent firing in the PFC. Here, we use a compartmental modeling approach to search for discriminatory features in the properties of incoming stimuli to a PFC pyramidal neuron and/or its response that signal which of these stimuli will result in persistent activity emergence. Furthermore, we use our modeling approach to study cell-type specific differences in persistent activity properties, via implementing a regular spiking (RS) and an intrinsic bursting (IB) model neuron. We identify synaptic location within the basal dendrites as a feature of stimulus selectivity. Specifically, persistent activity-inducing stimuli consist of activated synapses that are located more distally from the soma compared to non-inducing stimuli...

We have addressed the source and nature of the persistent neural activity that bridges the stimulus-free gap between the conditioned stimulus (CS) and unconditioned stimulus (US) during trace eyelid conditioning. Previous work has demonstrated that this persistent activity is necessary for trace eyelid conditioning: CS-elicited activity in mossy fiber inputs to the cerebellum does not extend into the stimulus-free trace interval, which precludes the cerebellar learning that mediates conditioned response expression. In behaving rabbits we used in vivo recordings from a region of medial prefrontal cortex (mPFC) that is necessary for trace eyelid conditioning to test the hypothesis that neurons there generate activity that persists beyond CS offset. These recordings revealed two patterns of activity during the trace interval that would enable cerebellar learning. Activity in some cells began during the tone CS and persisted to overlap with the US, whereas in other cells, activity began during the stimulus-free trace interval. Injection of anterograde tracers into this same region of mPFC revealed dense labeling in the pontine nuclei, where recordings also revealed tone-evoked persistent activity during trace conditioning. These data suggest a corticopontine pathway that provides an input to the cerebellum during trace conditioning trials that bridges the temporal gap between the CS and US to engage cerebellar learning. As such...

In this article, we analyze combined effects of LTP/LTD and synaptic scaling and study the creation of persistent activity from a periodic or chaotic baseline attractor. The bifurcations leading to the creation of new attractors have been detailed; this was achieved using a mean field approximation. Attractors encoding persistent activity can notably appear via generalized period-doubling bifurcations, tangent bifurcations of the second iterates or boundary crises, after which the basins of attraction become irregular. Synaptic scaling is shown to maintain the coexistence of a state of persistent activity and the baseline. According to the rate of change of the external inputs, different types of attractors can be formed: line attractors for rapidly changing external inputs and discrete attractors for constant external inputs.

Persistent activity is thought to mediate working memory during behavior. Can it also occur during sleep? We show that the membrane potential of medial entorhinal cortex layer III (MECIII) neurons, a gateway between neocortex and hippocampus, showed spontaneous, stochastic persistent activity in vivo in mice during Up-Down state oscillations (UDS). This persistent activity was locked to the neocortical Up states with a short delay, but persisted over several cortical UDS cycles. Lateral entorhinal (LECIII) neurons did not show significant persistence, and current injections similar to those used in vitro failed to elicit persistence in vivo, thus implicating network mechanisms. Hippocampal CA1 neurons’ activity was reduced during neocortical Up states, but was increased during MECIII persistent states. These results provide the first direct evidence for persistent activity in MECIII neurons in vivo, and reveal its contribution to cortico-hippocampal interaction, which could be involved in working memory and learning of long behavioral sequences during behavior, and memory consolidation during sleep.

Persistent neural activity, responses that outlast the stimuli that evoke them, plays an important role in neural computations and possibly in processes, such as working memory. Recent studies suggest that trace eyelid conditioning, which involves a temporal gap between the conditioned and unconditioned stimuli (the trace interval), requires persistent neural activity in a region of medial prefrontal cortex (mPFC). This persistent activity, which could be conveyed to cerebellum via a pathway through pons, may engage the cerebellum and allow for the expression of conditioned responses. Given the substantial reciprocity observed among many brain regions, it is essential to demonstrate that persistent responses in mPFC neurons are not simply a reflection of cerebellar feedback to the forebrain, leaving open the possibility that such responses could serve as input to the cerebellum. This concern is highlighted by studies showing that hippocampal learning-related activity is abolished by cerebellar inactivation. We inactivated the cerebellum while recording single-unit activity from the mPFC of rabbits trained with a forebrain-dependent trace eyelid conditioning procedure. We report that, whereas the responses of cells that show an onset of increased spike activity during the trace interval were abolished by cerebellar inactivation...

Neocortical network activity is generated through a dynamic balance between excitation, provided by pyramidal neurons, and inhibition, provided by interneurons. Imbalance of the excitation/inhibition ratio has been identified in several neuropsychiatric diseases, such as schizophrenia, autism and epilepsy, which also present with other cognitive deficits and symptoms associated with prefrontal cortical (PFC) dysfunction. We undertook a computational approach to study how changes in the excitation/inhibition balance in a PFC microcircuit model affect the properties of persistent activity, considered the cellular correlate of working memory function in PFC. To this end, we constructed a PFC microcircuit, consisting of pyramidal neuron models and all three different interneuron types: fast-spiking (FS), regular-spiking (RS), and irregular-spiking (IS) interneurons. Persistent activity was induced in the microcircuit model with a stimulus to the proximal apical dendrites of the pyramidal neuron models, and its properties were analyzed, such as the induction profile, the interspike intervals (ISIs) and neuronal synchronicity. Our simulations showed that (a) the induction but not the firing frequency or neuronal synchronicity is modulated by changes in the NMDA-to-AMPA ratio on FS interneuron model...

Technological advances have unraveled the existence of small clusters of co-active neurons in the neocortex. The functional implications of these microcircuits are in large part unexplored. Using a heavily constrained biophysical model of a L5 PFC microcircuit, we recently showed that these structures act as tunable modules of persistent activity, the cellular correlate of working memory. Here, we investigate the mechanisms that underlie persistent activity emergence (ON) and termination (OFF) and search for the minimum network size required for expressing these states within physiological regimes. We show that (a) NMDA-mediated dendritic spikes gate the induction of persistent firing in the microcircuit. (b) The minimum network size required for persistent activity induction is inversely proportional to the synaptic drive of each excitatory neuron. (c) Relaxation of connectivity and synaptic delay constraints eliminates the gating effect of NMDA spikes, albeit at a cost of much larger networks. (d) Persistent activity termination by increased inhibition depends on the strength of the synaptic input and is negatively modulated by dADP. (e) Slow synaptic mechanisms and network activity contain predictive information regarding the ability of a given stimulus to turn ON and/or OFF persistent firing in the microcircuit model. Overall...

Persistent activity and match effects are widely regarded as neuronal correlates of short-term storage and manipulation of information, with the first serving active maintenance and the latter supporting the comparison between memory contents and incoming sensory information. The mechanistic and functional relationship between these two basic neurophysiological signatures of working memory remains elusive. We propose that match signals are generated as a result of transient changes in local network excitability brought about by persistent activity. Neurons more active will be more excitable, and thus more responsive to external inputs. Accordingly, network responses are jointly determined by the incoming stimulus and the ongoing pattern of persistent activity. Using a spiking model network, we show that this mechanism is able to reproduce most of the experimental phenomenology of match effects as exposed by single-cell recordings during delayed-response tasks. The model provides a unified, parsimonious mechanistic account of the main neuronal correlates of working memory, makes several experimentally testable predictions, and demonstrates a new functional role for persistent activity.

Previous neuroimaging studies support a role for the medial temporal lobes in maintaining novel stimuli over brief working memory (WM) delays, and suggest delay period activity predicts subsequent memory. Additionally, slice recording studies have demonstrated neuronal persistent spiking in entorhinal cortex, perirhinal cortex (PrC), and hippocampus (CA1, CA3, subiculum). These data have led to computational models that suggest persistent spiking in parahippocampal regions could sustain neuronal representations of sensory information over many seconds. This mechanism may support both WM maintenance and encoding of information into long term episodic memory. The goal of the current study was to use high-resolution fMRI to elucidate the contributions of the MTL cortices and hippocampal subfields to WM maintenance as it relates to later episodic recognition memory. We scanned participants while they performed a delayed match to sample task with novel scene stimuli, and assessed their memory for these scenes post-scan. We hypothesized stimulus-driven activation that persists into the delay period—a putative correlate of persistent spiking—would predict later recognition memory. Our results suggest sample and delay period activation in the parahippocampal cortex (PHC)...

Cognitive functions supported by neurons in the prefrontal cortex (PFC) are disrupted by acute and chronic exposure to alcohol, yet little is known about the mechanisms that underlie these effects. In the present study, in vivo and in vitro electrophysiology was used to determine the effects of ethanol on neuronal firing and network patterns of persistent activity in PFC neurons. In vivo, ethanol (0.375-3.5 g/kg) dose-dependently reduced spike activity in the PFC measured with multi-electrode extracellular recording in the anesthetized rat. In an in vitro co-culture system containing slices of PFC, hippocampus and ventral tegmental area (VTA), ethanol (25-100 mM) decreased persistent activity of PFC neurons but had little effect on firing evoked by direct current injection. Persistent activity was often enhanced following ethanol washout and this effect was maintained in cultures lacking the VTA. A low concentration of the NMDA antagonist APV (5 μM) mimicked ethanol's inhibition of persistent activity with no change in activity following washout. Ethanol inhibition of spontaneous and VTA-evoked persistent activity was enhanced by the D1 dopamine receptor antagonist SCH23390. The results of this study show that ethanol inhibits persistent activity and spike firing of PFC neurons and that the degree of ethanol inhibition may be influenced by D1 receptor tone. Ethanol-induced alterations in the activity of deep-layer cortical neurons may underlie some of the behavioral effects associated with ethanol intake.

Working memory refers to the temporary storage of information and is strongly associated with the prefrontal cortex (PFC). Persistent activity of cortical neurons, namely the activity that persists beyond the stimulus presentation, is considered the cellular correlate of working memory. Although past studies suggested that this type of activity is characteristic of large scale networks, recent experimental evidence imply that small, tightly interconnected clusters of neurons in the cortex may support similar functionalities. However, very little is known about the biophysical mechanisms giving rise to persistent activity in small-sized microcircuits in the PFC. Here, we present a detailed biophysically—yet morphologically simplified—microcircuit model of layer V PFC neurons that incorporates connectivity constraints and is validated against a multitude of experimental data. We show that (a) a small-sized network can exhibit persistent activity under realistic stimulus conditions. (b) Its emergence depends strongly on the interplay of dADP, NMDA, and GABAB currents. (c) Although increases in stimulus duration increase the probability of persistent activity induction, variability in the stimulus firing frequency does not consistently influence it. (d) Modulation of ionic conductances (Ih...